The concentration of the Nterminal prohormone of brain natriuretic
peptide (NT-proBNP) [1] is often increased in patients with a reduced
renal function. The suggested diagnostic cutoffs in acute or subacute
heart failure [e.g., 300 pg/mL (66 pmol/L) and 125 pg/mL (27 pmol/L),
respectively] are therefore probably not applicable for hemodialysis
(HD) patients. A better approach may be to diagnose patients according
to changes from their baseline NT-proBNP concentrations. The changes in
patients who experience a clinical event can be compared with the
reference change value (RCV), which is based on the analytical CV (CVa)
and the within-person biological variation (CVi). The within-person
variation describes the natural fluctuations in the concentrations of
constituents in a stable situation. This study reports the CVa, CVi,
between-person biological variation (CVb), RCV, and index of
individuality (II) in HD patients and healthy individuals.

The Regional Committee for Medical and Health Research Ethics
approved the study. Informed written consent was obtained from 17
clinically stable patients who had been treated with HD at least twice
weekly for [greater than or equal to] 2 months. The patients had a
median age of 71 years, and 4 of the patients were women. Twenty healthy
individuals (50% women) with a median age of 61 years (range, 46-68
years) were included.

For the HD patients, 1 sample was collected before the midweek HD
treatment for 10 consecutive weeks. For the healthy individuals, a
weekly sample was collected (i.e., 7-day interval [+ or -] 1 day) for 10
consecutive weeks. Serum samples were frozen (-80 [degrees]C degrees)
and stored until analyzed on a Modular E (Roche Diagnostics) in a single
run with the Roche NT-proBNP assay.

The results of the Burnett test excluded 2 of the results as
analytical outliers. Six healthy individuals and 1 patient were excluded
because they had unmeasurable concentrations on >2 occasions. One
healthy individual was excluded on the basis of the Reed criterion. The
data for both HD patients and healthy individuals showed right-skewed
distributions. After natural logarithmic transformation, the residuals
of the data exhibited a gaussian distribution. The results of the
Cochrane and Bartlett tests showed variance homogeneity for the
analytical and within-person variances.

Two patients experienced exacerbation of heart failure during the
study and were excluded from the calculations; patient 3 had a single
episode of atrial fibrillation and dyspnea that led to admittance to the
hospital; patient 13 had increasing hypertension and dyspnea that led to
an increased dosage of antihypertensive and diuretic treatment and to
changes in the HD prescription.

We included ln-transformed data from 13 healthy individuals and 14
HD patients in calculating CVa, CVi, and CVb via nested ANOVA with Excel
software (version 2010; Microsoft). The RCV was calculated according to
Fokkema et al. (1) (95% CI, two-sided test) for ln-transformed data, and
the II was calculated as the SD of the CVa and CVi divided by the SD of
the CVb. Additionally, we calculated the RCV with a one-sided test to
illustrate the situation in which patients experience (increasing)
symptoms of heart failure.

Mean NT-proBNP concentrations, CVa, CVi, CVb, RCV, and II for
healthy individuals and HD patients are shown in Table 1. The 2 patients
who experienced clinical events both had NT-proBNP increases that were
higher than the calculated RCV (102%). The NTproBNP concentration
increased in patients 3 and 13 by 545% and 151%, respectively,
indicating that an unstable situation was present.

A limitation of this study was the relatively small number of
individuals included, although the numbers of individuals included and
measurements made were sufficient for calculating the biological
variation (2). A larger study that includes more patients with clinical
events would be necessary to validate the use and sensitivity of RCV for
diagnosing heart failure in HD patients.

Our study demonstrates that CVi values in stable HD patients (26%)
were similar to those of patients with stable heart failure (3, 4).
Specific diagnostic cutoffs are of little use if NT-proBNP is used for
diagnosing heart failure in HD patients, but the low II for NTproBNP
indicates that applying 8 values could be a possible solution. One study
showed that a 20% increase in NT-proBNP values had a sensitivity of 57%
and a specificity of 77% in predicting a congestive heart failure event
in HD patients (5). In the present study, a RCV (one-sided test) of +20%
included 70% of the changes, yielding a specificity of 70%. At a
specificity of 95%, the RCV (one-sided test, increasing values) is 80%.
We conclude that clinical actions for HD patients could be based on a
relatively small NT-proBNP change between 2 consecutive results,
depending on the pretest probability of a congestive cardiac event.

Author Contributions: All authors confirmed they have contributed
to the intellectual content of this paper and have met the following 3
requirements: (a) significant contributions to the conception and
design, acquisition of data, or analysis and interpretation ofdata; (b)
drafting or revising the article for intellectual content; and (c) final
approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No
authors declared any potential conflicts of interest.

(2.) Roraas T, Petersen PH, Sandberg S. CIs and power calculations
for within-person biological variation: effect of analytical
imprecision, number of replicates, number of samples, and number of
individuals. Clin Chem 2012; 58:1306-13.